Lipoxygenase products of arachidonic acid (eicosatetraenoic acid) display a diverse array of biological activities (Samuelsson, B., et al . Science 237:1171-1176 (1987)). At least four major classes of lipoxygenase-derived products of arachidonic acid metabolism have been identified: hydroperoxides (for example, 12-HPETE, 15-HPETE), non-peptidic leukotrienes (for example, LTB.sub.4), sulfidopeptide leukotrienes (for example LTC.sub.4, LTD.sub.4, and LTE.sub.4) and lipoxins. Generally, these classes are grouped together as lipoxygenase-derived eicosanoids (LDE); however, each class has a distinct profile of biological activities.
Lipoxins (lipoxygenase interaction products) are a novel series of arachidonic acid derived metabolites which have been characterized only recently (Serhan, C. N. et al., Biochem. Biophys. Res. Commun. 18:943-949 (1984); Serhan, C. N. et al., Proc. Natl. Acad. Sci. USA 5335-5339 (1984)). The distinguishing feature of the lipoxin chemical structure is the presence of a trihydroxy conjugated tetraene structure. At least two biologically active lipoxins have been characterized; LXA.sub.4 ((5S,6R,15S)-5,6,15-trihydroxy-7,9,13-trans-11-cis-eicosatetraenoic acid) and LXB.sub.4 ((5S,14R,15S)-5,14,15-trihydroxy-6,10,12-trans-8-cis-eicosatetraenoic acid (Serhan, C. N. et al., J. Biol. Chem. 261:16340-16345; Serhan, C. N. et al., Proc. Natl. Acad. Sci. USA 83:1983-1987 (1986)).
Very little is known about the biological roles or activities of the lipoxins. It has been suggested to use LXB.sub.4 to treat diseases characterized by inflammation mediated through the activation of neutrophils such as that found in asthma, arthritis, physical trauma and radiation exposure (Morris, J., U.S. Pat. No. 4,576,758; Samuelsson, B. et al., U.S. Pat. No. 4,560,514).
LXA.sub.4 has been shown to contract pulmonary smooth muscle (guinea pig lung), but not guinea pig ileum or trachea, and to relax (dilate) vascular smooth muscle at concentrations of less than 1 .mu.M (Dahlen, S.-E. et al., Acta Phvsiol. Scand. 130:643-647 (1987)). Topical administration of LXA.sub.4 to the hamster cheek pouch induces a pronounced arteriolar dilation, but does not change venular diameters (Dahlen, S.-E. et al., in Adv. Exper. Med. Biol.229: Chapter 9, pp. 107-130, 1988). LXA.sub.4 has also been shown to induce neutrophils to generate superoxide radicals, release elastase, and promote chemotaxis by leukocytes (Serhan, C. N. et al., in Prostaglandins, Leukotrienes and Liooxins, J. M. Bailey, ed., Plenum, N.Y., pp. 3-16, 1985).
It has been suggested to use LXA.sub.4 to induce the inflammatory response of neutrophils so as to provide an experimental model to evaluate the efficacy of compounds such as LXB.sub.4 derivatives in preventing this response (Samuelsson, B. et al., U.S. Pat. No. 4,560,514). It has also been suggested that LXA.sub.4 may exert some of its biological effects by binding to the LTD.sub.4 receptor (Jacques, C. A. J. et al., Br. J. Pharmacol. 95: 562-568 (1988)) and that LXA.sub.4 and LTD.sub.4 may even share a common receptor (Lefer, A. M. et al., Proc. Natl. Acad. Sci. USA 85:8340-8344 (1988)).
Slow-reacting substances of anaphylaxis (SRS-A) are considered to be the physiological mediators of anaphylactic and allergic reactions in animals. SRS-A consist primarily of a mixture of the LDE leukotrienes LTC.sub.4 and LTD.sub.4.
The release of SRS-A has also been implicated as the underlying cause of disorders of the mucociliary and cardiovascular system. SRS-A induced contraction of bronchial smooth muscle results in impairment of ventilatory function in allergic asthma. SRS-A induced impairment of mucus clearance leads to mucus plugging of the airways and bronchial hyper-reactivity seen in subjects with asthma. SRS-A induced pulmonary hypertension plays a role in cor polmonale, chronic bronchitis and emphysema. SRS-A induced negative inotropism, coronary vasoconstriction and increased vascular permeability have an effect on the cardiovascular system. SRS-A also participates in mediating the functional consequences of glomerular inflammatory injury (Badr, K.F., et al., J. Clin. Invest. 81:1702-1709 (1988)).
Inhibition of SRS-A, and amelioration of the physiological consequences of SRS-A, can occur either by blocking release of SRS-A or by blocking the actions of released SRS-A. Thus inhibition of the actions of SRS-A may be used to alleviate and treat the above disorders.
It is known to inhibit physiological responses to SRS-A by blocking the LTD.sub.4 receptor with LTD.sub.4 receptor antagonists. Sheard et al. have described a synthetic compound, FPL 55712, and derivatives thereof, which inhibit the SRS-A response by acting as LTD.sub.4 receptor antagonists (Sheard, P. et al., in The Develooment of Anti-Asthma Drugs, D. R. Buckle et al., eds., Butterworth, London, 1984, pp.133-158). However, FPL-55712 is short-acting. Other antagonists of SRS-A have been reported (for example, Gleason, J. G. et al., J. Med. Chem. 30:959-961 (1987)) including many which retain close structural similarity with FPL 55712 (Fleisch, J. H., et al., J. Pharmacol. Exp. Ther. 233:148 (1985); Young, R. N. et al., J. Med. Chem. 29:1573 (1986); O'Donnell, M. et al., Ann. Allergy 278 (1985). However, most of these compounds exhibit a low affinity for LTD.sub.4 receptors, are orally inactive or exhibit low bioavailability. The status of currently known LTD.sub.4 receptor antagonists has been recently reviewed (Lefer, A. M., ISI Atlas Sci. (Pharmacology) 2:109-115 (1988); Cashman, J. R. et al., Drugs of Today 24:723-732 (1988); Fleisch, J. H. et al., Ann. N. Y. Acad. Sci. 524:356-368 (1988); Musser, J. H. et al., Agents and Actions 18:332-341 (1986)).
Studies in human neutrophils, have established an inverse relation between the generation of lipoxins and leukotrienes following exposure of these cells to 15-HETE and the calcium ionophore A23187 (Serhan, C. N., in Advances in Prostaglandin, Thromboxane and Leukotriene Research, Samuelsson, B., et al. (eds.), Raven Press, N.Y., Volume 18). In addition, recent results indicate that mesangial cells can generate lipoxins from exogenous sources of LTA.sub.4 (Garrick, R., et al., Kidney Int. Proceedings 21st Annual Meeting of the American Society of Nephrology, Vol. 25, p. 292 (1989)), which may be provided by activated leukocytes (e.g., during transcellular metabolism). Thus, the local levels of these compounds may be elevated following the infiltration of leukocytes into the glomerulus.
Use of LTD.sub.4 receptor antagonists which are based on a natural product would be preferable to the use of completely synthetic compounds in that the natural products would ameliorate the physiological consequences of leukotriene-induced physiological injury with greater bioavailability and less toxicity than the synthetic inhibitors. Thus it is desirable to develop SRS-A antagonists which are natural compounds or derivatives thereof.